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JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in
XinWen Yu1, Richard H Kennedy, Shi J Liu
1Department of Pharmacology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
Abstract:
Interleukin (IL)-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway. However, mechanisms underlying IL-6-induced NO production remain unclear. JAK2/STAT3 and ERK1/2 are two well known signaling pathways activated by IL-6 in non-cardiac cells. However, these IL-6-activated pathways have not been identified in adult cardiac myocytes. In this study, we identified activation of these two pathways during IL-6 stimulation and examined their roles in IL-6-induced NO production and decrease in contractility of adult ventricular myocytes. IL-6 increased phosphorylation of STAT3 (at Tyr(705)) and ERK1/2 (at Tyr(204)) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h. Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor. The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but not AG490. Furthermore, IL-6 enhanced de novo synthesis of iNOS protein, increased NO production, and decreased cardiac contractility after 2 h of incubation. These effects were blocked by genistein and AG490 but not PD98059. We conclude that IL-6 activated independently the JAK2/STAT3 and ERK1/2 pathways, but only JAK2/STAT3 signaling mediated the NO-associated decrease in contractility.
Insights
Interleukin-6 (IL-6) reduces heart muscle contraction through nitric oxide (NO) signaling. The study found that the JAK2/STAT3 pathway, not ERK1/2, mediates IL-6
Area of Science:
- Cardiology
- Molecular Biology
- Cell Signaling
Background:
- Interleukin-6 (IL-6) negatively impacts cardiac contractility through a nitric oxide (NO)-dependent mechanism.
- The precise signaling pathways responsible for IL-6-induced NO production in cardiac cells are not fully understood.
- While Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways are known IL-6 targets in other cells, their role in adult cardiac myocytes was unidentified.
Purpose of the Study:
- To identify the IL-6-activated signaling pathways in adult ventricular myocytes.
- To investigate the involvement of these pathways in IL-6-induced NO production.
- To determine the role of these pathways in IL-6-mediated decreases in cardiac contractility.
Main Methods:
- Adult ventricular myocytes were stimulated with IL-6.
- Activation of JAK2/STAT3 and ERK1/2 pathways was assessed via phosphorylation.
- Nitric oxide (NO) production and cardiac contractility were measured.
- Specific inhibitors (genistein, AG490, PD98059) were used to block signaling pathways.
Main Results:
- IL-6 rapidly activated both JAK2/STAT3 and ERK1/2 pathways in adult ventricular myocytes.
- IL-6 stimulation led to increased de novo synthesis of inducible nitric oxide synthase (iNOS) protein, elevated NO production, and reduced cardiac contractility.
- Inhibition of the JAK2/STAT3 pathway (using genistein or AG490) blocked IL-6-induced NO production and the decrease in contractility.
- Inhibition of the ERK1/2 pathway (using PD98059) did not affect these IL-6-mediated effects.
Conclusions:
- IL-6 activates both JAK2/STAT3 and ERK1/2 signaling pathways independently in adult ventricular myocytes.
- The JAK2/STAT3 signaling pathway is the critical mediator of IL-6-induced NO production and subsequent reduction in cardiac contractility.
- ERK1/2 pathway activation by IL-6 in these cells does not contribute to the observed decrease in contractility via NO.